反应详情

温度

120 °C

Methyl 3-iodo-1H-indazole-5-carboxylate (30.7 g, 102 mmol), zinc cyanide (20.3 g, 173 mmol), zinc dust (4.05 g, 61.9 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (12 g, 15 mmol), and copper (I) iodide (19.7 g, 103 mmol) were combined in a 1 L round bottom flask. N,N-dimethylacetamide (500 mL) was added and the reaction mixture was purged with nitrogen for 10 minutes. The reaction was heated to 120° C. for 1 hour. The reaction was cooled to room temperature and was diluted with ethyl acetate (1 L), and allowed to stir for 20 minutes. The reaction mixture was filtered through a plug of Celite, rinsing with 500 mL ethyl acetate. The filtrate was added to a solution of saturated ammonium chloride and concentrated ammonium hydroxide (2 L) (prepared by adding ammonium hydroxide to a saturated aqueous solution of ammonium chloride until pH=8) and the biphasic solution was stirred vigorously for 1 hour. The resulting emulsion was filtered through a small pad of Celite. The layers were separated and the aqueous was extracted two additional times with ethyl acetate (1100 mL), each time filtering the resulting emulsion through Celite. The combined organic layers were washed with water (2×900 mL) and brine (900 mL), dried over sodium sulfate, filtered and concentrated. To the crude was added methanol (100 mL) and the mixture was stirred for 20 minutes. The resulting precipitate was filtered off and washed with methanol (10 mL). The filtrate was concentrated to give the title compound (13.2 g, 65%) as a solid. −ESI (M−H) 200.0; 1H NMR (400 MHz, DMSO-d6, δ): 8.43-8.45 (m, 1H), 8.05 (dd, J=8.8, 1.6 Hz, 1H), 7.85 (dd, J=8.9, 0.9 Hz, 1H), 3.88 (s, 3H).

1. customthe reaction mixture was purged with nitrogen for 10 minutes
2. temperatureThe reaction was cooled to room temperature
3. additionwas diluted with ethyl acetate (1 L)
4. filtrationThe reaction mixture was filtered through a plug of Celite
5. washrinsing with 500 mL ethyl acetate
6. additionThe filtrate was added to a solution of saturated ammonium chloride and concentrated ammonium hydroxide (2 L) (
7. customprepared
8. stirringwas stirred vigorously for 1 hour
9. filtrationThe resulting emulsion was filtered through a small pad of Celite
10. customThe layers were separated
11. extractionthe aqueous was extracted two additional times with ethyl acetate (1100 mL)
12. filtrationeach time filtering the resulting emulsion through Celite
13. washThe combined organic layers were washed with water (2×900 mL) and brine (900 mL)
14. dry with materialdried over sodium sulfate
15. filtrationfiltered
16. concentrationconcentrated
17. additionTo the crude was added methanol (100 mL)
18. stirringthe mixture was stirred for 20 minutes
19. filtrationThe resulting precipitate was filtered off
20. washwashed with methanol (10 mL)
21. concentrationThe filtrate was concentrated